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Table of Contents    
THE EDITORIAL DEBATE: PROS AND CONS
Year : 2016  |  Volume : 64  |  Issue : 1  |  Page : 25-26

Epidermal growth factor gene amplification in high grade gliomas


Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication11-Jan-2016

Correspondence Address:
Geeta Chacko
Department of Pathology, Christian Medical College, Vellore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.173672

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How to cite this article:
Chacko G. Epidermal growth factor gene amplification in high grade gliomas. Neurol India 2016;64:25-6

How to cite this URL:
Chacko G. Epidermal growth factor gene amplification in high grade gliomas. Neurol India [serial online] 2016 [cited 2019 Aug 17];64:25-6. Available from: http://www.neurologyindia.com/text.asp?2016/64/1/25/173672


The past decade has seen much progress in our understanding of the molecular pathology of gliomas.

Isocitrate dehydrogenase (IDH) 1 and 2 mutations are now recognized to discriminate biological classes of diffuse gliomas.[1] Gliomas with IDH mutations are associated with a better prognosis.[2],[3] Among the IDH mutant gliomas, 30–40% demonstrate 1p/19q codeletions; of the remaining, 94% exhibit tumor protein p53 (TP53) and alpha thalassemia/mental retardation syndrome X-linked (ATRX) mutations. These alterations are increasingly accepted as defining oligodendrogliomas and astrocytomas, respectively.[1] Among the glioblastomas (GBMs), most primary GBMs are IDH wild-type and most secondary GBMs are IDH mutated ones. Primary GBMs show additional molecular alterations in the tyrosine kinase receptor (TKR), retinoblastoma 1, and p53 families. In the TKR family, epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog deletion, and mutations of phosphatidylinositol-3-kinase are common. In contrast, secondary GBMs show a high frequency of IDH and TP53 mutations and ATRX inactivation.[4]

EGFR is a transmembrane glycoprotein that becomes autophosphorylated once it binds to its ligand. This induces subsequent activation of the signaling pathways involved in regulation of cell proliferation, differentiation, and survival. Approximately 40–50% of GBMs show amplification of EGFR and about half of these have variant III mutation. This mutation causes truncation of the receptor and leads to tyrosine kinase activity. There are controversial results on the prognostic relevance of EGFR amplification.[4],[5],[6],[7],[8],[9]

In a study published in this issue of Neurology India, a large series of high-grade gliomas have been studied using fluorescence in situ hybridization to assess the frequency of EGFR amplification. The authors found EGFR amplification in 34% of adult GBMs.[10]

The term GBM with an oligodendroglial component (GBM-O) has been used in the WHO 2007 classification for GBMs with areas similar to that seen in anaplastic oligodendrogliomas. It is, however, increasingly accepted that if these tumors exhibit 1p/19q codeletion, they are in fact anaplastic oligodendrogliomas.[11],[12] The current study found the frequency of EGFR amplification to be similar in those defined as GBM, and those that were diagnosed as GBM-O. None of the patients with GBM-O in their series had 1p/19q codeletion.[10] Therefore, by the current thinking, these too were in fact GBMs, and this explains the similarity in the frequency of EGFR amplification in the two groups.

Recently, TERT promoter mutations have also been found to be key molecular determinants of biologic behavior in gliomas.[1],[13] In a study published by The Cancer Genome  Atlas More Details, among WHO Grades II and III diffuse gliomas, 96% of cases with IDH mutation and 1p/19q codeletion showed TERT mutations while only 4% of IDH mutant gliomas without 1p/19q codeletion showed the mutation.[1] Simon et al., found TERT mutations more often in primary than secondary GBMS. They also reported an inverse correlation between IDH1/2 mutations and TERT promoter mutations.[14]

Although the diagnosis of gliomas so far was based primarily on the histological features, these recent developments have forced a relook at the classification of gliomas. As the number of clinically-relevant genetic alterations increase, there will most certainly be a transition toward the development of a molecular diagnostic panel for gliomas. In fact, the “integrated diagnosis” approach mooted by the International Society of Neuropathology-Haarlem Consensus Guidelines recommend the incorporation of molecular data as part of the layered format of reporting for gliomas.[15]

While there is no doubt that this approach which integrates molecular data with the histological picture is of utmost relevance to clinical treatment and outcome, the challenge we face in India is to be able to apply these norms uniformly at all centers of care. Perhaps centralized facilities that offer these services at a subsidized rate are the need of the hour.

 
  References Top

1.
Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cooper LA, et al. Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015;372:2481-98.  Back to cited text no. 1
    
2.
Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 2009;174:1149-53.  Back to cited text no. 2
    
3.
Metellus P, Coulibaly B, Colin C, de Paula AM, Vasiljevic A, Taieb D, et al. Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis. Acta Neuropathol 2010;120:719-29.  Back to cited text no. 3
    
4.
Crespo I, Vital AL, Gonzalez-Tablas M, Patino M Del C, Otero A, Lopes MC, et al. Molecular and genomic alterations in glioblastoma multiforme. Am J Pathol 2015;185:1820-33.  Back to cited text no. 4
    
5.
Benito R, Gil-Benso R, Quilis V, Perez M, Gregori-Romero M, Roldan P, et al. Primary glioblastomas with and without EGFR amplification: Relationship to genetic alterations and clinicopathological features. Neuropathology 2010;30:392-400.  Back to cited text no. 5
    
6.
Costa BM, Viana-Pereira M, Fernandes R, Costa S, Linhares P, Vaz R, et al. Impact of EGFR genetic variants on glioma risk and patient outcome. Cancer Epidemiol Biomarkers Prev 2011;20:2610-7.  Back to cited text no. 6
    
7.
Heimberger AB, Hlatky R, Suki D, Yang D, Weinberg J, Gilbert M, et al. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res 2005;11:1462-6.  Back to cited text no. 7
    
8.
Montano N, Cenci T, Martini M, D'Alessandris QG, Pelacchi F, Ricci-Vitiani L, et al. Expression of EGFRvIII in glioblastoma: Prognostic significance revisited. Neoplasia 2011;13:1113-21.  Back to cited text no. 8
    
9.
Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 2007;25:2288-94.  Back to cited text no. 9
    
10.
Shelly D, Epari S, Arora I, Pai T, Ahmed S, Moiyadi A, et al. Epidermal growth factor receptor (EGFR) gene amplification in high grade gliomas: Western Indian tertiary cancer centre experience. Neurol India 2016;64:115-20.  Back to cited text no. 10
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11.
Wesseling P, van den Bent M, Perry A. Oligodendroglioma: Pathology, molecular mechanisms and markers. Acta Neuropathol 2015;129:809-27.  Back to cited text no. 11
    
12.
Reuss DE, Sahm F, Schrimpf D, Wiestler B, Capper D, Koelsche C, et al. ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol 2015;129:133-46.  Back to cited text no. 12
    
13.
Nonoguchi N, Ohta T, Oh JE, Kim YH, Kleihues P, Ohgaki H. TERT promoter mutations in primary and secondary glioblastomas. Acta Neuropathol 2013;126:931-7.  Back to cited text no. 13
    
14.
Simon M, Hosen I, Gousias K, Rachakonda S, Heidenreich B, Gessi M, et al. TERT promoter mutations: A novel independent prognostic factor in primary glioblastomas. Neuro Oncol 2015;17:45-52.  Back to cited text no. 14
    
15.
Louis DN, Perry A, Burger P, Ellison DW, Reifenberger G, von Deimling A, et al. International Society of Neuropathology--Haarlem. International Society of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol 2014;24:429-35.  Back to cited text no. 15
    




 

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